T cell activation requires synergism between two signals: the first signal is generated by recognizing production of an antigen by a T cell antigen receptor (TCR) and is transduced into the cell via a CD3 molecule, the first signal determines the specificity of T cells in adaptive immune response; the second signal is generated by the interaction between co-stimulatory molecules on the surface of antigen-presenting cells (APCs) or target cells with corresponding co-stimulatory molecule receptors on the surface of T cells. Co-stimulatory signals stimulate antigen-specific T cells to proliferate and differentiate into effector T cells. In the absence of co-stimulatory signals, T cells will enter the non-responsive or autoimmune-tolerance state and even enter into programmed death.
OX40, also known as TNFRSF4, ACT35, CD134, IMD16 or TXGP1L, is a member of the TNFR receptor superfamily and is a type I transmembrane glycoprotein. OX40 is mainly expressed on activated CD4+T cells and CD8+T cells (Paterson et al. (1987) Mol Immunol 24: 1281-1290). The extracellular segment of OX40 consists of three cysteine-rich domains and one C-terminal incomplete CRD (Deanne M et al. (2006) Structure 14: 1321-1330). OX40 is a secondary co-stimulatory molecule. Unlike CD28, OX40 is not expressed on the surfaces of resting T-cells but is highly expressed 24-72 hours after T-cell activation. The ligand OX40L (TNFSF4, TXGP1, OX-40L, gp34 or CD252) of OX40 is a type II transmembrane glycoprotein and is expressed on activated antigen presenting cells such as dendritic cells, B cells, etc. (Godfrey, W R et al. (1994) J Exp Med 180: 757-762). The OX40/OX40L signal plays a very important role in the activation, proliferation and apoptosis inhibition of T cells. Studies show that activated OX40 antibodies can effectively promote the proliferation and activation of T cells and produce better anti-tumor effects (Brendan D. Curti et al. (2013) Cancer Res 73: 7189-7198).
The use of OX40-activating antibodies in combination with other methods of treating tumors is reviewed and described in detail by Stefanie N. Linch et al. (Stefanie N. Linch et al. (2015) frontiers in oncology 5: 1-14). It has also been reported that the survival of mice can be significantly prolonged when OX40-activating antibodies are used in combination with radiotherapy (Gough M J et al. (2010) J Immunother 33 (8): 798-809; Kjaergaard J et al. (2005) 103 (1): 156-164).
There remains a need in the art for anti-OX40 antibodies that are capable of binding with high affinity to OX40 and have OX40 agonist activity.